Date Posted: February 8, 2017
|Title||A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL|
|Journal||Clin Cancer Res|
|Date Published||2017 Jan 01|
PURPOSE: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER(+)/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER(+) breast cancer refractory to endocrine therapy.
EXPERIMENTAL DESIGN: Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing.
RESULTS: Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER(+)/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER(+) breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.
|Alternate Journal||Clin. Cancer Res.|
|PubMed Central ID||PMC5085926|
|Grant List||P30 CA016672 / CA / NCI NIH HHS / United States |
P50 CA098131 / CA / NCI NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States
P30 CA068485 / CA / NCI NIH HHS / United States
K23 CA127469 / CA / NCI NIH HHS / United States